ClinVar Genomic variation as it relates to human health

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu401 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9104431, 21722902, 25461735, 24507775). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in several individuals affected with familial hypercholesterolemia (PMID: 7573037, 19843101, 15701167, 11810272). This variant is also known as p.Leu380His or FH-Pori in the literature. ClinVar contains an entry for this variant (Variation ID: 3735). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with histidine at codon 401 of the LDLR protein (p.Leu401His). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and histidine.

The p.L401H pathogenic mutation (also known as c.1202T>A), located in coding exon 9 of the LDLR gene, results from a T to A substitution at nucleotide position 1202. The leucine at codon 401 is replaced by histidine, an amino acid with similar properties. This alteration (also referred to as L380H and FH-Pori), has been detected in several unrelated individuals with familial hypercholesterolemia (FH) and in FH cohorts (Koivisto UM et al. Am. J. Hum. Genet. 1995;57:789-97; Fouchier SW et al. Hum. Genet., 2001 Dec;109:602-15; Zakharova FM et al. BMC Med. Genet. 2005;6:6; Alver M et al. Genet Med. 2019 05;21(5):1173-1180; Meshkov A et al. Genes (Basel). 2021 01;12(1)). Another alteration at the same codon, p.L401V (c.1201C>G), has also been reported in association with FH (Leren TP et al. J. Intern. Med. 1997;241:185-94). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Based on the ACMG/AMP 2015 guidelines (Richards 2015), p.Leu401His variant has the following pathogenicity criteria: PM1- located in the EGF-precursor homology domain: YWTD repeat (Galicia-Garcia 2020); PM2 - detected in control samples of gnomAD v4.1.0 with a frequency of 0.0002480%; PM5 - missense variant at the same codon as a variant classified as pathogenic (c.1201С>G, p.Leu401Val (ClinVar ID 161267)) and predicts a different amino acid change; PP1_Strong - segregated with FH in 6 family members in three generations, including several family members in one generation (data from the Laboratory of Molecular Genetics, Moscow, Russia ); PP3; PP4-registered in patients with FH. According to the ClinGen guidelines for LDLR variant classification (Chora 2022): PS4 - variant has been found in ≥10 unrelated FH cases, including 28 FH case in Russia (Meshkov 2021); PM2 - has a PopMax MAF ≤ 0.0002 (0.02%) in gnomAD (0.0002480% v4.1.0 gnomAD); PM5 - missense variant at the same codon as a variant classified as pathogenic (c.1201С>G, p.Leu401Val (ClinVar ID 161267)) and predicts a different amino acid change; PP1_Strong -segregates with phenotype in 6 informative meioses in 1 family (5 relatives with this variant (LDL-C level >75th percentile) and 1 relative without this variant (LDL-C level<75th percentile); PP3 - REVEL score 0.952 (Liu 2011, Liu 2020); PP4 - identified in 28 proband with FH based on DLCN-criteria (data from the Laboratory of Molecular Genetics, Moscow, Russia (Meshkov 2021)). Based on a combination of criteria, this variant is pathogenic.